Regulatory T and activated T cells in the chronic unpredictable mild stress mice: sex differences and effects of treatments

Major Depressive Disorder (MDD) is strongly associated with immune dysregulation, which is characterized by excessive T-cell activation and a reduction in regulatory T cells (Tregs), leading to a disruption of immune homeostasis. Pharmacological treatments such as fluoxetine, simvastatin, curcumin, and S-adenosylmethionine (SAMe) have shown promise in alleviating depressive symptoms; however, their precise effects on immune responses remain inadequately understood. This study investigates the immune status of regulatory and activated T cells in MDD using the chronic unpredictable mild stress (CUMS) mouse model. Specifically, it examines how fluoxetine, simvastatin, curcumin, and SAMe modulate immune responses and mitigate depressive-like behaviors. Additionally, the study explores the impact of sex differences on immune responses. The study consisted of six groups, with 12 mice per group, ensuring equal male and female representation. These included a control group, a CUMS group, and groups treated with fluoxetine, simvastatin, curcumin, and SAMe. Behavioral changes were evaluated using sucrose preference and forced swimming tests. Immune cell markers from the spleen were analyzed by flow cytometry. The results showed that CUMS mice experienced a breakdown in immune tolerance due to Treg depletion and an increase in the CD154/CD152 ratio. Treatments with fluoxetine, simvastatin, curcumin, and SAMe improved depressive-like behaviors, with SAMe potentially exerting its antidepressant effects through the normalization of the CD154/CD152 ratio. Furthermore, sex differences played a critical role in immune responses: female mice exhibited lower levels of immune regulation and T-cell activation compared to males, along with a higher CD154/CD152 ratio, indicative of immune imbalance.